Caffey disease is associated with distinct arginine to cysteine substitutions in the proα1(I) chain of type I procollagen.

PURPOSE: Infantile Caffey disease is a rare disorder characterized by acute inflammation with subperiosteal new bone formation, associated with fever, pain, and swelling of the overlying soft tissue. Symptoms arise within the first weeks after birth and spontaneously resolve before the age of two years. Many, but not all, affected individuals carry the heterozygous pathogenic COL1A1 variant (c.3040C>T, p.(Arg1014Cys)). METHODS: We sequenced COL1A1 in 28 families with a suspicion of Caffey disease and performed ultrastructural, immunocytochemical, and biochemical collagen studies on patient skin biopsies. RESULTS: We identified the p.(Arg1014Cys) variant in 23 families and discovered a novel heterozygous pathogenic COL1A1 variant (c.2752C>T, p.(Arg918Cys)) in five. Both arginine to cysteine substitutions are located in the triple helical domain of the proα1(I) procollagen chain. Dermal fibroblasts (one patient with p.(Arg1014Cys) and one with p.(Arg918Cys)) produced molecules with disulfide-linked proα1(I) chains, which were secreted only with p.(Arg1014Cys). No intracellular accumulation of type I procollagen was detected. The dermis revealed mild ultrastructural abnormalities in collagen fibril diameter and packing. CONCLUSION: The discovery of this novel pathogenic variant expands the limited spectrum of arginine to cysteine substitutions in type I procollagen. Furthermore, it confirms allelic heterogeneity in Caffey disease and impacts its molecular confirmation.

Inspiratory muscle strength training improves lung function in patients with the hypermobile Ehlers-Danlos syndrome: A randomized controlled trial.

As exertional inspiratory dyspnea is a common disabling complaint in hypermobile Ehlers-Danlos syndrome (hEDS) often also known as joint hypermobility syndrome (JHS), we investigated inspiratory muscle (IM) strength in patients with hEDS, and we assessed the effects of IM training (IMT) on IM strength, lung function, and exercise capacity. A prospective evaluation of IM strength followed by a randomized controlled trial of IMT was performed in women with hEDS. Sniff nasal inspiratory pressure (SNIP) was used to routinely measure IM strength and IMT was carried out using a pressure threshold device. IM strength (main outcome), cardiopulmonary function, exercise capacity, and emotional distress of both the treated and control groups were evaluated at the start and at the end of the 6-week training period. IM strength was reduced (<80% of predicted) in 77% of patients (80/104). Lung function was normal, although 24% of patients had a higher forced expiratory vital capacity (FVC) than normal and 12% of patients had a higher total lung capacity (TLC) than normal. Both the IMT and control groups (n = 20) had similar baseline characteristics. Significant changes were noted only in the IMT group after IMT. At the end of the program, IMT improved SNIP (20%) (before: 41 ± 17 cm H2 O [28, 53] vs. after: 49 ± 18 cm H2 O [34;65]), six-minute walking distance (6MWD) (60 m) (455 ± 107 m [379,532] vs. 515 ± 127 m [408, 621]), and forced expiratory volume in one second (FEV1) (285 mL) (94 ± 14% pred [84,104] vs. 103 ± 11% pred [94, 112]). IM strength is significantly reduced in patients with hEDS. IMT improved IM strength, lung function, and exercise capacity. Our findings suggest that IMT should be added to usual care.

Hedgehog- and mTOR-targeted therapies for advanced basal cell carcinomas.

Basal cell carcinomas (BCCs) are the most frequent human cancer. Over 90% of all BCCs have a mutation in PTCH1 or smoothened, two conducting proteins of the Hedgehog pathway. They rarely progress deeply and metastasize; however, if they do, these advanced basal cell carcinoma become amenable to treatment by inhibiting the Hedgehog and the P13K-mTOR pathways. Such innovative drugs include vismodegib, cyclopamine, itraconazole, everolimus and a few other agents that are in early clinical development.

Protomyofibroblast Pathway in Early Thermal Burn Healing.

Wound healing following partial thickness thermal burns is commonly hampered by the risk of hypertrophic scarring. Skin myofibroblast (MF) density is commonly increased in postburn healing. The transition between fibroblast-like cells and α-smooth muscle actin (SMA)+ MF possibly begins with CD14+ monocytes, evolving to CD14+ CD34+ fibrocytes, followed by ß-SMA+ protomyofibroblast (PMF) maturation. Skin biopsies from 25 burn patients were collected about 1 and 4 weeks after injury. Immunohistochemistry was performed using monoclonal antibodies to α-SMA, ß-SMA, factor XIIIa, lysozyme, Mac 387, CD14, CD117 and Ulex europaeus agglutinin-1 (UEA-1). The set of Mac 387+ and CD14+ monocytes was accompanied by both CD34+ fibrocytes and factor XIIIa+ dendrocytes. By contrast, ß-SMA+ PMF were rare. Of note, α-SMA+ MF were more abundant at week 4 than at week 1 (p < 0.01). The UEA-1+ endothelial cells showed marked variations in their dermal distribution, irrespective of the densities in the other scrutinized cells. In conclusion, healing of partial thickness thermal burns involves a diversity of cell types including PMF. In the present samples, the PMF density remained low. © 2015 S. Karger AG, Basel.

Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta.

Whereas the vast majority of osteogenesis imperfecta (OI) is caused by autosomal dominant defects in the genes encoding type I procollagen, mutations in a myriad of genes affecting type I procollagen biosynthesis or bone formation and homeostasis have now been associated with rare autosomal recessive OI forms. Recently, homozygous or compound heterozygous mutations in BMP1, encoding the metalloproteases bone morphogenetic protein-1 (BMP1) and its longer isoform mammalian Tolloid (mTLD), were identified in 5 children with a severe autosomal recessive form of OI and in 4 individuals with mild to moderate bone fragility. BMP1/mTLD functions as the procollagen carboxy-(C)-proteinase for types I to III procollagen but was also suggested to participate in amino-(N)-propeptide cleavage of types V and XI procollagens and in proteolytic trimming of other extracellular matrix (ECM) substrates. We report the phenotypic characteristics and natural history of 4 adults with severe, progressive OI characterized by numerous fractures, short stature with rhizomelic shortening, and deformity of the limbs and variable kyphoscoliosis, in whom we identified novel biallelic missense and frameshift mutations in BMP1. We show that BMP1/mTLD-deficiency in humans not only results in delayed cleavage of the type I procollagen C-propeptide but also hampers the processing of the small leucine-rich proteoglycan prodecorin, a regulator of collagen fibrillogenesis. Immunofluorescent staining of types I and V collagen and transmission electron microscopy of the dermis show impaired assembly of heterotypic type I/V collagen fibrils in the ECM. Our study thus highlights the severe and progressive nature of BMP1-associated OI in adults and broadens insights into the functional consequences of BMP1/mTLD-deficiency on ECM organization.

Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis.

Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients. However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity.

Cyanoacrylate skin surface stripping and the 3S-Biokit advent in tropical dermatology: a look from Liège.

In the dermatopathology field, some simple available laboratory tests require minimum equipment for establishing a diagnosis. Among them, the cyanoacrylate skin surface stripping (CSSS), formerly named skin surface biopsy or follicular biopsy, represents a convenient low cost procedure. It is a minimally invasive method collecting a continuous sheet of stratum corneum and horny follicular casts. In the vast majority of cases, it is painless and is unassociated with adverse events. CSSS can be performed in subjects of any age. The method has a number of applications in diagnostic dermatopathology and cosmetology, as well as in experimental dermatology settings. A series of derived analytic procedures include xerosis grading, comedometry, corneofungimetry, corneodynamics of stratum corneum renewal, corneomelametry, corneosurfametry, and corneoxenometry.

In vivo skin fluorescence imaging in young Caucasian adults with early malignant melanomas.

BACKGROUND: Human cutaneous malignant melanoma (CMM) is an aggressive cancer showing a dramatic worldwide increase in incidence over the past few decades. The most prominent relative epidemiological increase has been disclosed in young women. The aim of the study was to assess the effects of chronic sun exposures in order to rate the extend of melanocytic stimulations in the vicinity of CMM. METHODS: The study was designed to evaluate the melanin distribution and density using ultraviolet light illumination. The present study was performed on surgical excision specimens of thin CMM lesion removed from the upper limbs of 55 Caucasian adults (37 women and 18 men). Two control groups comprised 23 men and 21 women of similar ages who had medium-size congenital melanocytic nevi, also present on the upper limbs. The peritumoral skin was scrutinized using a Visioscan(®) VC98 device, revealing the faint mosaic melanoderma (FMM) pattern that grossly indicates early signs of chronic photodamage in epidermal melanin units. RESULTS: The median extent of relative FMM was significantly higher in the CMM male group. By contrast, the CMM female group showed a reverse bimodal distribution in FMM size. Only 12/37 (32.5%) of the CMM female group had an increased FMM size, whereas 25/37 (67.5%) of females with CMM had a global FMM extent in the normal range, relative to the controls. CONCLUSION: Thin CMM supervening in young women appear unrelated to repeat photoexposure. Other mechanisms are possibly involved.

Streamlining cutaneous melanomas in young women of the Belgian Mosan region.

Sporadic cutaneous melanoma (SCM) has shown a dramatic increase in incidence in Caucasian populations over the past few decades. A particular epidemiological increase was reported in women during their childbearing age. In the Belgian Mosan region, a progressive unremitting increase in SCM incidence was noticed in young women for the past 35 years. The vast majority of these SCMs were of the superficial type without any obvious relationship with a large number of melanocytic nevi or with signs of frequent and intense sunlight exposures as disclosed by the extent in the mosaic subclinical melanoderma. A series of investigations pointed to a possible relationship linking the development of some SCM to the women hormonal status including the effect of hormonal disruptors. These aspects remain, however, unsettled and controversial. It is possible to differentiate and clearly quantify the SCM shape, size, scalloped border, and variegated pigmentation using computerized morphometry as well as fractal and multifractal methods.

Asymmetric facial skin viscoelasticity during climacteric aging.

BACKGROUND: Climacteric skin aging affects certain biophysical characteristics of facial skin. The purpose of the present study was to assess the symmetric involvement of the cheeks in this stage of the aging process. METHODS: Skin viscoelasticity was compared on both cheeks in premenopausal and post-menopausal women with indoor occupational activities somewhat limiting the influence of chronic sun exposure. Eighty-four healthy women comprising 36 premenopausal women and 48 early post-menopausal women off hormone replacement therapy were enrolled in two groups. The tensile characteristics of both cheeks were tested and compared in each group. A computerized suction device equipped with a 2 mm diameter hollow probe was used to derive viscoelasticity parameters during a five-cycle procedure of 2 seconds each. Skin unfolding, intrinsic distensibility, biological elasticity, and creep extension were measured. RESULTS: Both biological elasticity and creep extension were asymmetric on the cheeks of the post-menopausal women. In contrast, these differences were more discrete in the premenopausal women. CONCLUSION: Facial skin viscoelasticity appeared to be asymmetric following menopause. The possibility of asymmetry should be taken into account in future studies of the effects of hormone replacement therapy and any antiaging procedure on the face in menopausal women.

Dermal ultrastructure in collagen VI myopathy.

The COL VI mutations are responsible for a spectrum of myopathies. The authors report cutaneous ultrastructural alterations in a patient with COL6A2 myopathy. The changes include variations in size of collagen fibrils, flower-like sections of collagen fibrils, as well as thickening of vessel and nerve basement membranes. Electron microscopy of a skin biopsy contributes to the diagnosis of COL VI myopathies.

Dormancy of growth-stunted malignant melanoma: sustainable and smoldering patterns.

The presentations of primary and metastatic cutaneous malignant melanoma (CMM) are very diverse. Evidence increasingly indicates that single CMM cells spread to distant sites quite early during cancer progression and are soon eliminated before they become clinically detectable. However bulky metastases which appear at a later stage might derive from some of these early neoplastic cells. It seems that local CMM single cell micro-metastases commonly predict sentinel lymph node involvement without overtly reflecting CMM progression to bulky visceral metastases. This study is intended to review the current understanding of the mechanisms underlying two CMM presentations. The first is the long interval, apparently disease-free, with persistent CMM dormancy, which may precede overt metastatic growth. Immunosurveillance may induce dormancy in single CMM cells disseminated in the body by blocking their proliferation cycle. The second is the so-called CMM smoldering phenomenon, which is marked by an alternate progression and regression of CMM locally with metastases that wax and wane for long periods of time over restricted skin areas. These very diverse patterns of CMM progression are likely to be ascribable to a number of biological factors, including the activation of CMM stem cells, and the combined phenotypic heterogeneity and variability in proliferative amplification in CMM cell clusters. Furthermore an adequate stimulation of CMM immune-surveillance and the induction of a specific stromal structure and vascular response are required. In this context, most early CMM tumors are in part controlled by lymphocyte-mediated responses before they become clinically detectable. However both the role of immune-surveillance and the mechanisms underlying both persistent and smoldering CMM dormancy remain unclear.

Ehlers-Danlos Syndrome Type VIII: A Rare Cause of Leg Ulcers in Young Patients.

Ehlers-Danlos syndrome type VIII (EDS-VIII) is a very rare autosomal dominant disease characterized by early-onset periodontitis associated with features of Ehlers-Danlos syndrome. We report a 32-year-old man whose chronic leg ulcer led to the diagnosis of EDS-VIII. He had severe periodontitis with complete loss of permanent teeth and skin fragility with thin skin, atrophic scars, and brownish atrophic pretibial plaques. Leg ulcer is not a prominent feature of EDS-VIII. We suggest adding EDS-VIII to the list of rare diseases accounting for chronic leg ulcers, if this case report prompts others to report leg ulcers associated with EDS-VIII.

Cyclic catamenial dermatoses.

Circulating sex hormones follow major fluctuations during the ovarian cycle. The so-called premenstrual syndrome represents a global condition grouping the diversity of catamenial disorders. At the skin level, the sebaceous gland activity is obviously modulated by these endocrine fluctuations. In addition, a series of pathological manifestations take place simultaneously in some women. Among them, the most frequent skin condition is represented by catamenial acne. Concurrently, the autoimmune progesterone dermatitis refers to a diversity of skin alterations resulting from an immune reaction to progesterone. It is present under variable clinical aspects. A series of other recurrent skin conditions are not specifically induced but are merely exacerbated at the end of the ovarian cycle.

Scrutinizing skinfield melanin patterns in young Caucasian women.

INTRODUCTION: When using adequate wavelength illumination and high resolution recordings, Caucasian skin color appears uneven. The patterns of faint mosaic melanoderma (FMM) are diverse and possibly related to the risk of skin cancer development. AREAS COVERED: The current peer-reviewed publications about objective methods quantifying FMM are revisited. The images from the Visioscan® and Visioface® Quick devices are computerized in order to record the ultraviolet light-enhanced visualization (ULEV) and the color-enhanced visualization (CEV) of the skin. Previously published data regarding the FMM are gathered in 20 odd Caucasian women. Seven FMM patterns are distinguished. They appear expressed differently according to body regions, but the mean gray level appears more uniform. EXPERT OPINION: The combination of larger subclinical melanotic macules and ivory spots during early adulthood is apparently associated with an increased risk for non-melanoma skin cancers.

The skin landscape in diabetes mellitus. Focus on dermocosmetic management.

BACKGROUND: Some relationships are established between diabetes mellitus (DM) and a series of cutaneous disorders. Specific dermatoses are markers for undiagnosed DM. Other disorders represent supervening complications in an already treated DM patient. OBJECTIVE: To review the information about dermocosmetic care products and their appropriate use in the management and prevention of dermatoses related to DM. METHOD: The peer-reviewed literature and empiric findings are covered. Owing to the limited clinical evidence available for the use of dermocosmetics, a review of the routine practices and common therapies in DM-related dermatoses was conducted. RESULTS: Some DM-related dermatoses (acanthosis nigricans, pigmented purpuric dermatosis) are markers of macrovascular complications. The same disorders and some others (xerosis, Dupuytren's disease) have been found to be more frequently associated with microangiopathy. Other skin diseases (alopecia areata, vitiligo) were found to be markers of autoimmunity, particularly in type 1 DM. Unsurprisingly, using dermocosmetics and appropriate skin care has shown objective improvements of some DM-related dermatoses, such effects improve the quality of life. The most common skin manifestations of DM fall along continuum between "dry skin," xerosis, and acquired ichthyosis, occurring predominately on the shins and feet. Dermocosmetic products improve the feeling of well-being for DM patients.

Scleroderma: skin stiffness assessment using the stress-strain relationship under progressive suction.

INTRODUCTION: A few non-invasive biometrological methods are available for monitoring skin stiffening in systemic scleroderma. Among them, the Cutometer® is used for years by several clinical teams. OBJECTIVES: To revisit the microscopic structure of the dermal fibrous networks in scleroderma and the relationship with changes in viscoelasticity. METHODS: The suction method delivered by the Cutometer® was applied following the progressive stress-vs-strain modality. RESULTS: The test procedure was sensitive enough to document the initial progression steps of acroscleroderma. Four stages were thus identified including i) the incipient, ii) the progressive, iii) the overt, and iv) the regressive acroscleroderma. CONCLUSION: The non-invasive determination of skin biomechanical functions is relevant both in routine clinical practice and in antisclerotic drug development. It is complementary although not a substitute for the determination of selected serum biomarkers.

Revisiting the cutaneous impact of oral hormone replacement therapy.

Menopause is a key point moment in the specific aging process of women. It represents a universal evolution in life. Its initiation is defined by a 12-month amenorrhea following the ultimate menstrual period. It encompasses a series of different biologic and physiologic characteristics. This period of life appears to spot a decline in a series of skin functional performances initiating tissue atrophy, withering, and slackness. Any part of the skin is possibly altered, including the epidermis, dermis, hypodermis, and hair follicles. Hormone replacement therapy (oral and nonoral) and transdermal estrogen therapy represent possible specific managements for women engaged in the climacteric phase. All the current reports indicate that chronologic aging, climacteric estrogen deficiency, and adequate hormone therapy exert profound effects on various parts of the skin.

Dermal ultrastructure in low Beighton score members of 17 families with hypermobile-type Ehlers-Danlos syndrome.

The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural abnormalities of EDSH and BJHS among different families. Skin of 23 EDSH, 27 BJHS, and 41 asymptomatic subjects from 17 families was examined using transmission electron microscopy. Similar ultrastructural abnormalities were found irrespective of the Beighton score. Flower-like collagen fibrils represented the key change and elastic fibers were altered as well. Beighton score is a clinical parameter rating joint mobility that appeared unrelated to quantitative and qualitative collagen ultrastructural alterations in the skin. Some EDSH family members fit with BJHS diagnosis. BJHS possibly represents a mild variant of EDSH.

Challenging regional psoriasis and ustekinumab biotherapy: impact of the patterns of disease.

In some patients, psoriasis appears refractory to many treatments, particularly when the disease is confined to some specific body regions. In this respect, palmoplantar psoriasis and palmoplantar pustulosis are possibly related conditions in their immunopathomechanisms involving Il-12, IL-23, and Th17. Nail psoriasis and scalp psoriasis are two other particular psoriasis manifestations. Accordingly, ustekinumab was tested in a few of these patients. The present paper is limited to peer-reviewed case reports. Data were not supported by bioinstrumental assessments and controlled trials. Overall, they are indicative of potential efficacy. The cost-effectiveness and the risk-benefit assessments merit further investigations.